Direct Access to Chiral β-Fluoroamines with Quaternary Stereogenic Center through Cooperative Cation-Binding Catalysis

Article abstract of DOI:10.1002/chem.201605637

A direct route to chiral β-fluoroamines with tetrasubstituted C?F centers through the organocatalytic Mannich reaction of α-fluoro cyclic ketones and α-amidosulfones by using a chiral oligoethylene glycol as a cation-binding catalyst and KF as a base is reported. For most substrates, nearly perfect enantioselectivities were achieved even at very high temperatures (>80 °C). The salient features of this process include a) a transition-metal-free and operationally simple procedure, b) direct use of α-amidosulfones as bench-stable precursors of sensitive imines, c) direct enolization of racemic α-fluoro cyclic ketones, and d) excellent stereoselectivity up to 99 % enantiomeric excess and >20:1 diastereoselectivity (anti/syn). Thus, this protocol is easily scalable and provides a new approach for the synthesis of biologically relevant products with tetrasubstituted C?F centers. Furthermore, this protocol was also successfully extended to generate C?Cl and C?Br quaternary stereogenic centers.

Full text of DOI:10.1002/chem.201605637

A Journal of
Accepted Article
Title: Direct Access to Chiral β-Fluoroamines with Quaternary
Stereogenic Center via Cooperative Cation Binding Catalysis
Authors: Venkataramasubramanian Vaithiyanathan, Mun Jong Kim,
Yidong Liu, Hailong Yan, and Choong Eui Song
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201605637
Link to VoR: http://dx.doi.org/10.1002/chem.201605637
Supported by

10.1002/chem.201605637
Chemistry - A European Journal
COMMUNICATION
Direct Access to Chiral β-Fluoroamines with Quaternary Stereogenic
Center via Cooperative Cation Binding Catalysis
Venkataramasubramanian Vaithiyanathan,[a] Mun Jong Kim,[a] Yidong Liu,[b] Hailong Yan*,[b] and Choong Eui
Song*,[a]
Abstract: Reported herein is a direct route for chiral β-fluoroamines
possessing tetrasubstituted C-F centers through the organocatalytic
Mannich reaction of α-fluoro cyclic ketones and α-amidosulfones using a
chiral oligoEG as a cation binding catalyst with KF as a base. In most
substrates, nearly perfect enantioselectivites were achieved even at very
high temperatures (>80 oC). The salient features of this process include (a)
a transition metal free and operationally simple procedure, (b) direct use of
α-amidosulfones as bench-stable precursors of sensitive imines, (c) direct
enolization of racemic α-fluoro cyclic ketones and (d) excellent
stereoselectivity up to 99% ee and >20:1 diastereoselectivity (anti:syn).
Thus, this protocol is easily scalable and provides a new approach for the
syntheses of some biologically relevant products possessing tetrasubstituted
C-F centers. Futhermore, this protocol was also successfully extended to
generate C-Cl and C-Br quaternary stereogenic centers.
workers utilized the dinuclear Zn/Prophenol catalyst for direct
Mannich reaction to furnish highly entio-enriched β-fluoroamines with
“anti” diastereoselectivity.[7b]
We recently developed[9] chiral oligoEG catalysts
1 as
cooperative cation binding catalysts[10] and successfully applied them
to a desilylative kinetic resolution of silyl protected secondary
alcohols,[9e] asymmetric Strecker synthesis of α-aminoacids,[9d] and
kinetic resolution of β-sulfonyl ketones through enantioselective β-
elimination.[9f] In continuation of our research on exploring other
challenging catalytic asymmetric reactions using 1 (in Scheme 1b), we
wished to develop direct catalytic enantioselective Mannich reactions,
allowing direct use of α-fluoro cyclic ketones as donors together with
α-amidosulfones[11] instead of sensitive corresponding imines, as well
as directly affording β-amino α-fluoro cyclic ketones possessing
tetrasubstituted C-F centers. We believed that our cation binding
catalyst system was ideally suited for this reaction, in which potassium
fluoride, upon activation by the chiral cation-binding catalyst, would
enable the generation of the corresponding imine substrate in situ from
α-amidosulfones as well as the enolate substrate in situ from ketones.
Subsequently, the catalyst would bring both activated reacting partners
together in proximity, resulting in a product with high asymmetric
induction.
Fluorine incorporated molecules have received a great deal of interest
in life sciences.[1] Due to the higher electronegativity and oxidation
potential of the fluorine atom, it can improve the pharmacological
properties of a bioactive molecule by altering its lipophilicity,
metabolic stability and bioavailability compared to the non-fluorinated
parent compound.[1] Indeed, a nearly 20% increase in the number of
fluorinated drugs have occurred in the market during the last decade.[2]
Consequently, fluorinated analogues of bioactive molecules are now
important tools in pharmaceutical research. Among them, molecules
containing β-fluoroamine moieties are of great importance in medicinal
chemistry due to their privileged structural motif.[3] It is well known
that the presence of fluorine at the β-position lowers the pKa of
neighbouring amines, thus enhancing binding interactions and
improving metabolic stability. This leads to increased penetration
through the central nervous system (CNS) of a biological system.[4] As
a consequence, the discovery of a new method for the synthesis of
chiral β-fluoroamine derivatives is one of the rapidly growing research
areas for synthetic chemists.[5] In particular, chiral β-fluoroamine
compounds with quaternary stereogenic C-F centers[6] are expected to
have very interesting pharmaceutical properties. In view of this
challenging task, very recently, Tan[7a], Trost[7b] and their co-workers
utilized catalytic asymmetric Mannich reactions with α-fluoro
cycloketones and aromatic aldimines to construct β-fluoroamines with
quaternary C-F stereocenters (Scheme 1a).[8] Tan et.al successfully
utilized chiral guanidine as an organocatalyst to afford chiral β-
fluoramine derivatives with the “syn” diastereomer as the major
product.[7a] Complementary to this work, quite recently, Trost and co-
Bu
Bu
O
X
NHBoc
Ar
O
X
N
N
F
Ms
H
H
F
N
+
(10 mol%)
R
Ar
-20 oC, ClCH2CH2Cl, 4Å MS
n
n
X = -CH2- (n = 0,1)
syn Mannich[ref]
up to 98% ee
X = O (n = 1)
up to 5.2:1 d.r.
O
O
(R,R)-Prophenol (10 mol%)
Boc
H
F
NHBoc
N
Et2Zn (20 mol%)
+
F
R
R
Ar
Ar
Mannich[ref]
anti
80 oC, THF, 3Å MS
n
n
n = 1,2
up to >99% ee
up to >20:1 d.r.
b) This work
Song's chiral oligoEG catalyst
I
I
O
O
O
O
OH
HO
I
I
(R)-1
O
O
X
NHBoc
Y
n
NHBoc
Y
1
(R)- (10 mol%) / KF
Ar
+
25-100 oC, o-xylene
R
Ar
SO2Ph
X
n
X = -CH2- (n = 0 - 2)
X = O, S (n = 1)
Y = F, Cl, Br
anti Mannich
up to >99% ee
up to >20:1 d.r.
[a]
[b]
Prof. C. E. Song, V. Vaithiyanathan, M. J. Kim
Department of Chemistry, Sungkyunkwan University
Suwon, 440-746 (Korea)
E-mail: s1673@skku.edu
Prof. H. Yan, Y. Liu
Innovative Drug Research Centre (IDRC),
School of Pharmaceutical Sciences, Chongqing University,
55 Daxuecheng South Rd., Chongqing 401331 (China)
E-mail: yhl198151@cqu.edu.cn
Scheme 1. Enantioselective synthesis of β-fluoroamines with quaternary stereogenic
C-F center
Here, we report a transition metal free straightforward route to
highly enantio- and diastereo-enriched β-fluoroamine derivatives
possessing quaternary C-F centers through direct organocatalytic
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201605637
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COMMUNICATION
Mannich reaction with α-fluoroketones and α-amidosulfones using a
cation-binding catalyst (Scheme 1b). Excellent enantio- and
diastereoselectivity was obtained with a variety of fluoro cyclic
ketones and α-amidosulfones even at very high temperatures (>80 C).
This protocol was also successfully extended to generate C-Cl and C-
Br quaternary stereogenic centers.
the reaction temperature and concentration. Upon further optimization,
we were pleased to observe that an increase in the reaction rate was
paralleled by an increase in temperature and concentration without
diminishing the enatioselectivity or the diastereoselectivity (entries 9-
11). Finally, at 80 °C and in very high concentration (1 M), the reaction
proceeded with full conversion (84% isolated yield) within 24 h, with
excellent enantioselectivity (95% ee) and the diastereoselectivity (1:7
for anti) (entry 11).[12] Further increase in the temperature to 100 °C
showed only a comparable decrement in enantioselectivity to 94% ee,
indicating a relatively high stability for the transition state (entry 12).
With the optimal catalytic conditions in hand, we then evaluated
the generality of our protocol with α-amidosulfones as the electrophilic
o
Table 1. Optimization of reaction condition
partner. As shown in Scheme 2,
a variety of aromatic and
heteroaromatic Boc-α-amidosulfones were successfully reacted with
racemic α-fluoro cyclic ketones 2 in the presence of KF (3 equiv.) and
catalyst (R)-1b (10 mol%) in o-xylene (1 M). Regardless of the
electronic and steric nature of the substituents on the aromatic ring, all
α-amidosulfones 3 as imine precursors tested in this study were
smoothly converted to the corresponding Mannich products 4a-4j in
excellent yields and almost perfect ees. Heteroaromatic substrates such
as 3-furyl (4g) and 3-thienyl (4h) also gave excellent yields and
stereoselectivities (Scheme 2).
Time
[h]
Temp. Conv. ee
Entry Catalyst Solvent
2 [M]
dr[d]
[oC]
rt
[%][b] [%][c]
1
(R)-1a
(R)-1b
(R)-1c
(R)-1d
(R)-1b
(R)-1b
(R)-1b
(R)-1b
(R)-1b
(R)-1b
(R)-1b
(R)-1b
toluene
toluene
toluene
toluene
THF
0.1
0.1
0.1
0.1
0.1
0.1
0.1
66
48
48
48
48
48
48
48
50
50
24
20
30
21
12
9
85
>99
0
1:7
2
rt
n.d.[e]
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
1:5
O
O
NHBoc
R
3
rt
cat (R)-1 (10 mol%)
F
n
NHBoc
SO2Ph
F
+
4
rt
96
89
99
99
99
99
>99
95
94
KF (3 equiv)
R
o-xylene (1 M)
5
rt
10
14
20
54
74
96
98
100
n
2
3
80 o
C
4
R = aryl, heteroaryl
n = 0, 1 or 2
6
dioxane
CH2Cl2
rt
7
rt
O
F
NHBoc
O
NHBoc
O
NHBoc
F
F
8
o-xylene 0.1
o-xylene 0.1
o-xylene 0.25
o-xylene 1.0
o-xylene 1.0
rt
9
70
70
80
100
F
CN
10
11
12
1:10
1:7
4a
4b
4c
84%, 95% ee (anti)
dr = 1:7 (syn:anti)
74%, 95% ee (anti)
dr = 1:4 (syn:anti)
91%, 93% ee (anti)
dr = 1:5 (syn:anti)
1:5
O
NHBoc
O
NHBoc
O
NHBoc
F
F
F
[a] Unless otherwise indicated, reactions were performed with 2a (0.1 mmol), 3a
(0.15 mmol), KF (3 equiv.) and catalyst (R)-1 (10 mol%). [b] Conversion was
determined by 1H NMR integration. [c] The % ee was determined by HPLC analysis
using a chiral stationary phase. [d] The relative and absolute configuration of the
major diasteromer was unambiguously assigned as “anti” and [(S)C-F, (S)C-NHBoc],
respectively, by comparison of the coupling constant and the retention time of HPLC
with the literature data.[7b] [e] not determined.
O
O
NO2
OMe
4d
4e
4f
91%, 95% ee (anti)
dr = 1:5 (syn:anti)
85%, 93% ee (anti)
dr = 1:8 (syn:anti)
79%, 95% ee (anti)
dr = 1:7(syn:anti)
O
NHBoc
O
NHBoc
O
NHBoc
F
F
F
O
Our initial investigation of the asymmetric Mannich reaction of
α-amidosulfone 3a with α-fluorotetralone 2a as a model substrate is
summarized in Table 1. The effect of the catalyst structure ((R)-1a-d)
on the reaction outcome was first investigated with a catalyst loading
of 10 mol% in toluene at room temperature. As we expected, based on
our knowledge of the catalytic performance of chiral oligoEGs 1a-
1d,[9] catalyst 1b was found to be the best in terms of the
enantioselectivity of the major diastereomer (99% ee, entry 2). In
further experiments, different solvents were examined (entry 2 and
entries 5-8). Toluene and xylenes proved to be the optimal choice. In
non-polar solvents such as toluene and o-xylene, 54% of starting
material 2 (Table 1, Entries 2 and 8) was converted after 48 h to
product with 99% ee, whereas in polar aprotic solvents (Table 1,
entries 5-7), <30% conversion was attained even after running the
reaction for more than 48 h. Although we observed the formation of
the desired Mannich product with perfect enantiopurity (>99% ee), the
reaction proceeded too slowly (Table 1, entries 2 and 8). To improve
the % conversion, we next attempted different conditions by changing
S
F
4g
4h
4i
92%, 97% ee (anti)
dr = 1:9 (syn:anti)
90%, 96% ee (anti)
dr = 1:20< (syn:anti)
73%, 89% ee (anti)
dr = 1:7 (syn:anti)
O
NHBoc
O
O
NHBoc
NHBoc
F
F
F
F
4j
4k
4l
51%, 88% ee (anti)
dr = 1:5 (syn:anti)
68%, 90% ee (anti)
dr = 1:4 (syn:anti)
36%, 88% ee (anti)
dr = 1:3.7 (syn:anti)
Scheme 2. Substrate scope for the Mannich reaction of 2 to α-amidosulfone 3.[a] [a]
Reactions were performed with 2 (0.3 mmol), 3 (0.45 mmol), and (R)-1b (10 mol%) in
o-xylene (1M) at 80 °C for 24 h (in case of 4a-d), 36 h (in case of 4e) . The yield was
determined after chromatographic purification, and the % ee was determined by HPLC
analysis using a chiral stationary phase. Diastereomeric ratio was determined by 1H
NMR.
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10.1002/chem.201605637
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COMMUNICATION
(R)-1 (10 mol%)
KF (3.0 equiv)
NHBoc
SO2Ph
O
NHBoc
O
We then investigated other types of α-fluorocyclic cyclic ketones
with five to seven membered carbocyclic rings for this reaction. As
Cl
Cl
+
o-xylene
25 oC, 4 d
shown in Scheme 2, fluorobenzosuberones
2 (n = 2) and
F3C
CF3
8
7
3
fluoroindanones (n = 0) also proved to be excellent Mannich donors,
furnishing the Mannich product 4i-4l in high to excellent
enantioselectivity (88 to 95% ee).[13]
The substrate scope was also successfully extended to
chromanones and thiochromanones, which are present in many
biologically active natural compounds.[14] α-Fluorochromanones and α-
fluorothiochromanones were smoothly converted to the corresponding
Mannich products 6a-f together with excellent enantioselectivity (up to
99% ee for major diastereomer) and reasonable diastereomeric ratio
(up to 7:1 for anti) (Scheme 3).
64%, 99% ee
>20:1dr
1
(R)- (10 mol%)
O
NHBoc
SO2Ph
O
NHBoc
Br
KF (3.0 equiv)
Br
+
o-xylene
25 oC, 48 h
F3C
CF3
10
9
3
80%, 99% ee
>20:1 dr
Scheme 4. Mannich reaction of 7 or 8 to α-amidosulfone 3.[a] [a] Reactions were
performed with 7 or 8 (0.5 mmol), 3 (1.5 equiv.), and (R)-1 (10 mol%) in o-xylene
(5.0 mL) at 25 °C.
O
O
X
NHBoc
R
cat (R)-1 (10 mol%)
F
NHBoc
SO2Ph
F
+
and up to >20:1 d.r. (anti:syn)). As shown in the proposed mechanism,
the cation (K+)-binding to the catalyst is critical to induce high
reactivity and high enantioselectivity in the enantio-determining step
by the formation of the chiral cage. To support this proposed reaction
mechanism, we conducted an in situ electrospray ionization mass
spectroscopy (ESI-MS) analysis of the reaction mixture (see the
Supporting Information). Gratifyingly, some proposed intermediates
could be seen in the measurements of ESI-MS (positive ion mode). The
signals at m/z 1228.8168, m/z 1593.7529, m/z 1451.9171 and m/z
KF (3 equiv)
R
o-xylene (1 M)
X
80 o
C
5
3
6
X = O or X
R = aryl, heteroaryl
NHBoc
NHBoc
NHBoc
O
O
O
O
O
F
F
F
O
O
O
O
6a, 96%,
95%ee (anti)
93%ee (syn)
6b, 99%,
93%ee (syn)
93%ee (anti)
dr = 1:3.7 (syn:anti)
6c, 94%,
97%ee (anti)
dr = 1:7 (syn:anti)
1614.1870 correspond to [I – F-], [II – F-], [III – PhSO2 ] and [IV],
-
dr = 1:2 (syn:anti)
respectively.
O
NHBoc
O
NHBoc
O
NHBoc
F
F
F
O
O
O
I
S
S
S
O
O
I
O
K+
O
6d[b], 99%,
97%ee (anti)
6e[b], 65%,
98%ee (anti)
6f[c], 88%,
H
O
O
H
I
F
I
KF
>99% ee (major dr)
Complex I
3a
-
92%ee (syn)
95%ee (syn)
dr = 1:6 (syn:anti)
I
observed [ - F ] : m/ z 1228.8168
(R)-1
-
I
cacld [ - F ] : m/z 1228.8166
dr = 1:3.7 (syn:anti)
dr = 1:4 (syn:anti)
4a
HF
Scheme 3. Substrate scope for the Mannich reaction of 5 to α-amidosulfone 3.[a] [a]
Reactions were performed with 5 (0.3 mmol), 3 (0.45 mmol), and (R)-1b (10 mol%) in
o-xylene (1M) at 80 °C for 28 h. [b] Reactions were performed with 5 (0.2 mmol), 3
(0.3 mmol), and (R)-1b (10 mol%) in o-xylene (1M) at 70 °C for 36 h. [c] Reactions
were performed with 5 (0.3 mmol), 3 (0.45 mmol), and (R)-1b (10 mol%) in o-xylene
(1M) at 70 °C for 28 h.
I
I
O
O
I
O
O
I
O
O
K+
K+
O
O
O
H O
O
H
O
H
H
O
F
I
I
I
I
F
O
H
O
S
R
Ph
N
O
N
O
t
R
OtBu
O Bu
IV
Complex
observed [ ] : m/z 1614.1870
cacld [IV] : m/ z 1614.9733
II
Complex
IV
observed [II - F-] : m/ z 1593.7529
cacld [II - F-] : m/ z 1593.9263
I
O
O
S
I
O
KSO2Ph
We were further interested in expanding our optimized catalytic
condition to the Mannich reaction of other halogenated cyclic ketones
such as 7 and 9 to generate C-Cl and C-Br quaternary stereogenic
centers[15] in the corresponding products, respectively. The preliminary
results of this significant transformation are as shown in Scheme 4.
Delightfully, both the ketones 7 and 9 furnished the Mannich products
8 and 10, respectively, in quantitative yield with almost perfect
enantio- and diastereoselectivity at room temperature (Scheme 4).
Based on our experimental results and our previous reports
regarding cation binding catalysis, the plausible reaction mechanism is
illustrated in Figure 1. At the first step, complex I is formed by the
complexation of KF with the catalyst, which then engages with
amidosulfone to form the complex II. Subsequently, elimination of the
sulfinate group from amidosulfone affords an imine activated through
hydrogen bonding as dictated in complex III. The subsequent
coordination of potassium enolate (generated in-situ from cyclic
ketones with KF) to the catalyst is followed by its addition to the imine
to provide the enantio- and diastereo-enriched adducts (up to 99% ee
K+
O
O
O
O
H
O
H
HF
I
OK
F
I
N
t
O
Ph
R
O Bu
III
Complex
F
soluble '
'
observed [III - PhSO2-] : m/ z 1451.9171
cacld [ - PhSO2-] : m/z 1451.9174
2a
III
Figure 1. A proposed reaction mechanism and observation of the intermediates
In summary, we have developed
a transition metal free
straightforward strategy for the synthesis of highly enantio- and
diastereo-enriched β-fluoroamine derivatives possessing quaternary C-
F centers through direct organocatalytic Mannich reactions with
fluoroketones and α-amidosulfones using a cation-binding catalyst and
KF as a base. Excellent enantio- and diastereoselectivity were obtained
with a variety of fluoro cyclic ketones and α-amidosulfones even at a
very high temperature (80 oC), perhaps due to the conformational
stability of the transition state. The salient features of this process
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10.1002/chem.201605637
Chemistry - A European Journal
COMMUNICATION
2011, 47, 4593–4623; f) K. W. Quasdorf, L. E. Overman, Nature 2014, 516,
181–191.
include (a) a transition metal free and operationally simple procedure,
(b) direct use of α-amidosulfones as bench-stable precursors of
sensitive imines, enabling the use of a broad scope of α-amidosulfones,
(c) direct enolization of racemic α-fluoro cyclic ketones and (d)
excellent stereoselectivity with up to 99% ee and >20:1
diastereoselectivity (anti:syn). This protocol was also successfully
extended to generate C-Cl and C-Br quaternary stereogenic centers.
Thus, we believe that this protocol can provide a new approach for the
syntheses of diverse biologically relevant products possessing
quaternary stereogenic C-halogen centers. The extension of this
strategy to the synthesis of quaternary carbon in acyclic systems is
currently underway in our laboratory.
[7]
[8]
a) Y. Zhao, Y. Pan, H. Liu, Y. Yang, Z. Jiang, C.-H. Tan, Chem. Eur. J. 2011,
17, 3571–3574; b) B. M. Trost, T. Saget, A. Lerchen, C.-I. Hung, Angew.
Chem., Int. Ed. 2016, 55, 781–784.
Efficient routes to chiral -fluoroamines bearing tertiary C-F centers via
asymmetric Mannich reactions of carbonyls with imines have also recently
developed independently by the Shibasaki[8a] and Zhao groups[8b]. see.: a) L.
Brewitz, F. A. Arteaga, L. Yin, K. Alagiri, N. Kumagai, M. Shibasaki, J. Am.
Chem. Soc. 2015, 137, 15929–15939; b) H.-Y. Wang, K. Zhang, C.-W. Zheng,
Z. Chai, D.-D. Cao, J.-X. Zhang, G. Zhao, Angew. Chem. Int. Ed. 2015, 54,
1775–1779.
[9]
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E. Song, Angew. Chem. Int. Ed. 2009, 48, 7683–7686; Angew. Chem. 2009,
121, 7819–7822; b) H. Yan, H. B. Jang, J.-W. Lee, H. K. Kim, S. W. Lee, J. W.
Yang, C. E. Song, Angew. Chem. Int. Ed. 2010, 49, 8915–8917; Angew. Chem.
2010, 122, 9099–9101; c) H. Yan, J.-S. Oh, C. E. Song, Org. Biomol. Chem.
2011, 9, 8119–8121; d) H. Yan, J. S. Oh, J.-W. Lee, C. E. Song, Nat. Commun.
2012, 3, 1212; e) S. Y. Park, J.-W. Lee, C. E. Song, Nat. Commun. 2015, 6,
7512; f) L. Li, Y. Liu, Y. Peng, L. Yu, X. Wu, H. Yan, Angew. Chem. Int. Ed.
2016, 55, 331–335; g) J.-W. Lee, M. T. Oliveira, H. B. Jang, S. Lee, D. Y. Chi,
D. W. Kim, C. E. Song, Chem. Soc. Rev. 2016, 45, 4638–4650.
Acknowledgements
This study was supported by the Fundamental Research Funds for the
Central Universities in China (Grant No: 0236015205004), the
Scientific Research Foundation of China (Grant No: 0236011104404),
Graduate Scientific Research and Innovation Foundation of Chongqing,
China (CYB16032) and the Ministry of Science, ICT, and Future
Planning in Korea (Grant No: NRF-2014R1A2A1A01005794 and
NRF-2016R1A4A1011451).
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Keywords: cation-binding catalysis • chiral oligoethylene glycol
catalyst • Mannich reaction • β-fuoroamines • quaternary stereogenic
center
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10.1002/chem.201605637
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
V. Vaithiyanathan, M. J. Kim Y. Liu, H.
Yan* and C. E. Song*
Page No. – Page No.
Direct Access to Chiral β-
Fluoroamines with Quaternary
Stereogenic Center via Cooperative
Cation Binding Catalysis
A highly efficient asymmetric Mannich reaction of α-fluoro cyclic ketones with α-amidosulfones as the imine surrogates, affording β-
fluoroamines possessing quaternary stereogenic C-F center in excellent stereoselectivity (up to 99% ee and up to >20:1 d.r.
(anti:syn)), is achieved by using a Song’s chiral oligoEG as a cation binding catalyst and KF as a base. Catalysis in a confined chiral
cage, generated in-situ by binding the potassium cation with the polyether backbone is the key factor in inducing high reactivity and
enantioselectivity.
This article is protected by copyright. All rights reserved.